9,9-Alkylene-3,7-diazabicyclononane compounds of formula I and their pharmacological activities are known from published European Patent No. EP 103,833 and the corresponding U.S. Pat. No. 4,550,112, and Finnish Patent No. FI 76,338. Compounds of formula I are a sub-group of the 9,9-N,N′-tetra-substituted 3,7-diazabicyclo[3.3.1]nonane compounds described in the aforementioned patent specifications and can be prepared by the methods described therein. The aforementioned patent specifications disclose that the compounds have useful cardio-active properties, particularly oxygen-saving effects and effects on the heart rate and heart rhythm in general, and are distinguished by a high physiological tolerance. Thus, the compounds show a satisfactory anti-arrhythmic action even at low doses. Moreover, the undesired negative effect on the contractile power of the heart is extremely low; i.e. the compounds have a particularly favorable ratio of anti-arrhythmic or the refractory period of the heart prolonging activities, to negative inotropic secondary activities.
Moreover, as described in Burow et al., U.S. Pat. No. 5,164,401, the compounds also have a pronounced diuretic effect with a favorable ratio between sodium and potassium excretion.
Furthermore, special salts of the 3,7-diazabicyclo[3,3,1]-nonane compounds and their manufacture, in particular of 9,9-alkylene-3,7-diazabicyclo[3,3,1]nonane compounds are described in U.S. Pat. No. 5,324,732. Thus, U.S. Pat. No. 5,324,732 describes fumaric acid salts of these compounds containing 1.5 moles of fumaric acid per mole of the compound.
Atrial fibrillation (AFib) is the most common sustained cardiac arrhythmia requiring hospitalization, and affects millions of people worldwide. The prevalence of AFib increases with age and in the presence of structural heart disease, it is also slightly more common in men than women. AFib is associated with significant mortality and morbidity and impacts significantly on quality of life. Restoration of normal sinus rhythm (NSR) in patients with these arrhythmias may improve their hemodynamic condition, relieve symptoms, and probably reduce embolic risk. Although this may be achieved using DC cardioversion, the technique has limitations such as the need for general anesthesia and hospitalization. Accordingly, pharmacological conversion has been proposed as an attractive alternative; a variety of anti-arrhythmic drugs have been tested for this purpose. However, many of these agents have important side effects such as the potential for pro-arrhythmia, impairment of LV function, or extracardiac unwanted effects. Consequently, there is a need to develop new anti-arrhythmic drugs not only with good clinical efficacy but also with a favorable safety profile.
Tedisamil is a novel class III anti-arrhythmic agent that blocks multiple potassium-channels and slows sinus rate. It prolongs both atrial and ventricular action potential duration by blocking the transient outward Ito, the ATP-dependent IK-ATP, and the delayed rectifier potassium currents IKr, IKs, and IKu. Tedisamil prolongs action potential duration more strongly in the atria than the ventricles. Unlike other selective potassium-channel blocking drugs, tedisamil does not exhibit reverse rate-dependent effects on atrial refractoriness, which makes it far less likely to be pro-arrhythmic. Finally, tedisamil also possesses significant anti-anginal and anti-ischemic properties. The present prospective, randomized, controlled trial evaluated the efficacy and safety of tedisamil for rapid conversion of AFib or AFlu.